# US 10,118,946 B2 · Agonists of guanylate cyclase and their uses

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- Number: US 10,118,946 B2
- Document ID: US10118946B2
- Status: Granted
- Kind: B2
- Application number: 15/622,526
- Filed: 2017-06-14
- Published: 2017-12-07
- Granted: 2018-11-06
- Earliest claimed: 2013-03-15
- Assignees: Synergy Pharmaceuticals, Inc.
- Applicants: Synergy Pharmaceuticals, Inc.
- Inventors: Kunwar Shailubhai
- Web page: https://patentgrep.com/patent/US10118946B2

## CPC

- C07K 7/06: having 5 to 11 amino acids
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention provides novel guanylate cyclase C (GC-C) agonists and their therapeutic use. The agonists may be used either alone or in combination with one or more additional agents.

## Claims

### Claim 1

A method for treating a condition that responds to enhanced cGMP levels in a patient comprising administering to said patient a therapeutically effective amount of a peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-38, 50-94, 119, and 120, wherein said peptide is administered in an amount sufficient to increase water transport in the gastrointestinal tract and induce cGMP production in a gastrointestinal epithelial cell.

### Claim 2

A method for preventing or treating a condition selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), non-ulcer dyspepsia, chronic intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, constipation, chronic constipation, constipation associated with use of opiate pain killers, post-surgical constipation, constipation associated with neuropathic disorders, gastroesophageal reflux disease (GERD), Celiac disease, gastroparesis, heartburn, poor gastrointestinal motility, congestive heart failure, hypertension, benign prostatic hyperplasia (BPH), colon cancer, lung cancer, bladder cancer, liver cancer, salivary gland cancer or skin cancer, bronchitis, tissue inflammation, organ inflammation, respiratory inflammation, asthma, COPD, lipid metabolism disorders, biliary disorders, cardiovascular disease, obesity and an endocrine disorder comprising administering to a patient in need thereof a therapeutically effective amount of a peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-38, 50-94, 119, and 120.

### Claim 3

A method of colonic cleansing, comprising administering to a subject in need thereof an effective amount of a peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-38, 50-94, 119, and 120.

### Claim 4

A method of increasing cGMP production in a cell comprising contacting said cell with a peptide consisting essentially of the sequence of any one of SEQ ID NOs: 1-38, 50-94, 119, and 120.

### Claim 5 (depends on 1)

The method of claim 1, wherein said peptide is Asn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16 (SEQ ID NO: 1), Asn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Ser16 (SEQ ID NO: 32), Asn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Thr16 (SEQ ID NO: 119), Asn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Tyr16 (SEQ ID NO: 120), dAsn1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-dLeu16 (SEQ ID NO: 17), or pyGlu1-Asp2-Aad3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16 (SEQ ID NO: 56).

### Claim 6 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a cGMP-dependent phosphodiesterase inhibitor.

### Claim 7 (depends on 6)

The method of claim 6, wherein said cGMP-dependent phosphodiesterase inhibitor is administered either concurrently or sequentially with said guanylate cyclase receptor agonist.

### Claim 8 (depends on 6)

The method of claim 6, wherein said cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of sulindac sulfone, zaprinast, motapizone, vardenafil, and sildenafil.

### Claim 9 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of at least one anti-inflammatory agent.

### Claim 10

The method of 9, wherein said anti-inflammatory agent is a steroid or nonsteroid anti-inflammatory drug (NSAID).

### Claim 11 (depends on 3)

The method of claim 3, further comprising administering to said subject an effective amount of L-glucose, lubiprostone (Amitiza), prucalopride, an agent for treating chronic constipation, or any combination thereof.